The goal of this project is to develop innovative image-guided EMT inhibition by targeting the proteins in the key biological event associated with metastasis using RNAi to effectively treat metastatic BC. Metastatic breast cancer is the leading cause of the premature deaths of women diagnosed with the disease in the United States. Currently, there are limited treatment options for the patients whose breast cancer becomes multidrug resistance and relapsed disease. Epithelial-mesenchymal transition (EMT) is a key biological event associated with breast cancer metastasis and multidrug resistance. We have identified several markers of breast cancer EMT for imaging metastatic breast cancer and for effective treatment of metastatic breast cancer by inhibiting cancer cell EMT and resensitizing the cells to chemotherapy under imaging guidance. In this project, we will develop molecular MRI and DCE-MRI to direct the inhibition of BC EMT using targeted lipid siRNA nanoparticles in treating metastatic BC. We will develop targeted multifunctional lipid siRNA delivery systems to down-regulate the expression of key proteins that promote cancer cell EMT for effective inhibition of BC EMT and treatment of metastatic BC alone and in combination with chemotherapy under imaging guidance. Non-invasive and timely assessment of therapeutic efficacy of the new therapeutic regimens using the imaging technologies will guide the optimization of the delivery systems and treatment protocols to achieve the best possible outcomes and to cure the disease. The specific aims of this project are 1) to first establish molecular imaging technologies for non-invasive image-guided inhibition of EMT with targeted multifunctional siRNA delivery systems in treating metastatic breast cancer; 2) to evaluate and optimize image-guided silence of EMT-regulatory genes and inhibition of BC EMT and metastasis using targeted multifunctional siRNA delivery systems; 3) to evaluate and optimize image-guided combination therapy of the multifunctional siRNA delivery systems and chemotherapeutics in treating TNBC. Substantial preliminary data have been obtained to demonstrate the effectiveness of the proposed image-guided therapeutic regimens in treating metastatic breast cancer. Our long-term goal is to develop an image-guided therapeutic approach to effectively treat life-threatening metastatic BC.